Synthesis of Mixed Phosphonate Esters and Amino Acid-Based Phosphonamidates, and Their Screening as Herbicides.

While organophosphorus chemistry is gaining attention in a variety of fields, the synthesis of the phosphorus derivatives of amino acids remains a challenging task. Previously reported methods require the deprotonation of the nucleophile, complex reagents or hydrolysis of the phosphonate ester. In this paper, we demonstrate how to avoid these issues by employing phosphonylaminium salts for the synthesis of novel mixed n-alkylphosphonate diesters or amino acid-derived n-alkylphosphonamidates. We successfully applied this methodology for the synthesis of novel N-acyl homoserine lactone analogues with varying alkyl chains and ester groups in the phosphorus moiety. Finally, we developed a rapid, quantitative and high-throughput bioassay to screen a selection of these compounds for their herbicidal activity. Together, these results will aid future research in phosphorus chemistry, agrochemistry and the synthesis of bioactive targets.

A temperature-sensitive and interferon-silent Sendai virus vector for CRISPR-Cas9 delivery and gene editing in primary human cells.

The transformative potential of gene editing technologies hinges on the development of safe and effective delivery methods. In this study, we developed a temperature-sensitive and interferon-silent Sendai virus (ts SeV) as a novel delivery vector for CRISPR-Cas9 and for efficient gene editing in sensitive human cell types without inducing IFN responses. ts SeV demonstrates unprecedented transduction efficiency in human CD34+ hematopoietic stem and progenitor cells (HSPCs) including transduction of the CD34+/CD38-/CD45RA-/CD90+(Thy1+)/CD49f high stem cell enriched subpopulation. The frequency of CCR5 editing exceeded 90% and bi-allelic CCR5 editing exceeded 70% resulting in significant inhibition of HIV-1 infection in primary human CD14+ monocytes. These results demonstrate the potential of the ts SeV platform as a safe, efficient, and flexible addition to the current gene-editing tool delivery methods, which may help to further expand the possibilities in personalized medicine and the treatment of genetic disorders.

Synthesis and unambiguous NMR characterization of linear and branched N-alkyl chitosan derivatives.

Chitosan, sourced from abundant chitin-rich waste streams, emerges as a promising candidate in the realm of future functional materials and chemicals. While showing numerous advantageous properties, chitosan sometimes falls short of competing with today's non-renewable alternatives. Chemical derivatization, particularly through N-alkylation, proves promising in enhancing hydrophobic functionalities. This study synthesizes fifteen chitosan derivatives (degree of substitution = 2-10 %) using an improved reductive amination method. Next, selective depolymerization through acid hydrolysis reduced the chain rigidity imposed by the polymer backbone. This facilitated unambiguous structural characterization of the synthesized compounds using a combination of common NMR techniques. Two potential side reactions are identified for the first time, emphasizing the need for detailed structural information to unlock the true potential of these derivatives in future applications. HYPOTHESIS: The increase in chain mobility induced by the selective depolymerization of aliphatic N-alkyl chitosan derivatives allows for an unambiguous NMR characterization.

De novo antibody discovery in human blood from full-length single B cell transcriptomics and matching haplotyped-resolved germline assemblies.

Immunoglobulin (IGH, IGK, IGL) loci in the human genome are highly polymorphic regions that encode the building blocks of the light and heavy chain IG proteins that dimerize to form antibodies. The processes of V(D)J recombination and somatic hypermutation in B cells are responsible for creating an enormous reservoir of highly specific antibodies capable of binding a vast array of possible antigens. However, the antibody repertoire is fundamentally limited by the set of variable (V), diversity (D), and joining (J) alleles present in the germline IG loci. To better understand how the germline IG haplotypes contribute to the expressed antibody repertoire, we combined genome sequencing of the germline IG loci with single-cell transcriptome sequencing of B cells from the same donor. Sequencing and assembly of the germline IG loci captured the IGH locus in a single fully-phased contig where the maternal and paternal contributions to the germline V, D, and J repertoire can be fully resolved. The B cells were collected following a measles, mumps, and rubella (MMR) vaccination, resulting in a population of cells that were activated in response to this specific immune challenge. Single-cell, full-length transcriptome sequencing of these B cells resulted in whole transcriptome characterization of each cell, as well as highly-accurate consensus sequences for the somatically rearranged and hypermutated light and heavy chain IG transcripts. A subset of antibodies synthesized based on their consensus heavy and light chain transcript sequences demonstrated binding to measles antigens and neutralization of measles live virus.

Structure-guided mutagenesis of Henipavirus receptor-binding proteins reveals molecular determinants of receptor usage and antibody-binding epitopes.

Nipah virus (NiV) is a highly lethal, zoonotic Henipavirus (HNV) that causes respiratory and neurological signs and symptoms in humans. Similar to other paramyxoviruses, HNVs mediate entry into host cells through the concerted actions of two surface glycoproteins: a receptor-binding protein (RBP) that mediates attachment and a fusion glycoprotein (F) that triggers fusion in an RBP-dependent manner. NiV uses ephrin-B2 (EFNB2) and ephrin-B3 (EFNB3) as entry receptors. Ghana virus (GhV), a novel HNV identified in a Ghanaian bat, uses EFNB2 but not EFNB3. In this study, we employ a structure-informed approach to identify receptor-interfacing residues and systematically introduce GhV-RBP residues into a NiV-RBP backbone to uncover the molecular determinants of EFNB3 usage. We reveal two regions that severely impair EFNB3 binding by NiV-RBP and EFNB3-mediated entry by NiV pseudotyped viral particles. Further analyses uncovered two-point mutations (NiVN557SGhV and NiVY581TGhV) pivotal for this phenotype. Moreover, we identify NiV interaction with Y120 of EFNB3 as important for the usage of this receptor. Beyond these EFNB3-related findings, we reveal two domains that restrict GhV binding of EFNB2, confirm the HNV-head as an immunodominant target for polyclonal and monoclonal antibodies, and describe putative epitopes for GhV- and NiV-specific monoclonal antibodies. Cumulatively, the work presented here generates useful reagents and tools that shed insight to residues important for NiV usage of EFNB3, reveal regions critical for GhV binding of EFNB2, and describe putative HNV antibody-binding epitopes. IMPORTANCE: Hendra virus and Nipah virus (NiV) are lethal, zoonotic Henipaviruses (HNVs) that cause respiratory and neurological clinical features in humans. Since their initial outbreaks in the 1990s, several novel HNVs have been discovered worldwide, including Ghana virus. Additionally, there is serological evidence of zoonotic transmission, lending way to concerns about future outbreaks. HNV infection of cells is mediated by the receptor-binding protein (RBP) and the Fusion protein (F). The work presented here identifies NiV RBP amino acids important for the usage of ephrin-B3 (EFNB3), a receptor highly expressed in neurons and predicted to be important for neurological clinical features caused by NiV. This study also characterizes epitopes recognized by antibodies against divergent HNV RBPs. Together, this sheds insight to amino acids critical for HNV receptor usage and antibody binding, which is valuable for future studies investigating determinants of viral pathogenesis and developing antibody therapies.

Rxn-INSIGHT: fast chemical reaction analysis using bond-electron matrices.

The challenge of devising pathways for organic synthesis remains a central issue in the field of medicinal chemistry. Over the span of six decades, computer-aided synthesis planning has given rise to a plethora of potent tools for formulating synthetic routes. Nevertheless, a significant expert task still looms: determining the appropriate solvent, catalyst, and reagents when provided with a set of reactants to achieve and optimize the desired product for a specific step in the synthesis process. Typically, chemists identify key functional groups and rings that exert crucial influences at the reaction center, classify reactions into categories, and may assign them names. This research introduces Rxn-INSIGHT, an open-source algorithm based on the bond-electron matrix approach, with the purpose of automating this endeavor. Rxn-INSIGHT not only streamlines the process but also facilitates extensive querying of reaction databases, effectively replicating the thought processes of an organic chemist. The core functions of the algorithm encompass the classification and naming of reactions, extraction of functional groups, rings, and scaffolds from the involved chemical entities. The provision of reaction condition recommendations based on the similarity and prevalence of reactions eventually arises as a side application. The performance of our rule-based model has been rigorously assessed against a carefully curated benchmark dataset, exhibiting an accuracy rate exceeding 90% in reaction classification and surpassing 95% in reaction naming. Notably, it has been discerned that a pivotal factor in selecting analogous reactions lies in the analysis of ring structures participating in the reactions. An examination of ring structures within the USPTO chemical reaction database reveals that with just 35 unique rings, a remarkable 75% of all rings found in nearly 1 million products can be encompassed. Furthermore, Rxn-INSIGHT is proficient in suggesting appropriate choices for solvents, catalysts, and reagents in entirely novel reactions, all within the span of a second, utilizing nothing more than an everyday laptop.

Complete genome sequence of Mycobacterium smegmatis phage Rummer, a subcluster A3 actinophage.

Bacteriophage Rummer is a siphovirus morphology actinophage isolated from Mycobacterium smegmatis. Rummer has a 50,908 base pair genome encoding 89 predicted protein-coding genes and three tRNAs. Based on gene content similarity to sequenced actinobacteriophages, Rummer is assigned to phage subcluster A3.

Synthesis and bioactivity of psilocybin analogues containing a stable carbon-phosphorus bond.

Psilocybin analogues have been synthesized comprising a non-hydrolysable P-C bond to evaluate the biological activity and the selectivity towards 5-HT2AR, 5-HT2BR and the TNAP receptor. No activity was observed towards the phosphatase, however all compounds showed good binding affinity for 5-HT2AR and 5-HT2BR and one compound showed a higher selectivity towards 5-HT2AR than psilocin.

The Application of Porous Organic Polymers as Metal Free Photocatalysts in Organic Synthesis.

Concerns about increasing greenhouse gas emissions and their effect on our environment highlight the urgent need for new sustainable technologies. Visible light photocatalysis allows the clean and selective generation of reactive intermediates under mild conditions. The more widespread adoption of the current generation of photocatalysts, particularly those using precious metals, is hampered by drawbacks such as their cost, toxicity, difficult separation, and limited recyclability. This is driving the search for alternatives, such as porous organic polymers (POPs). This new class of materials is made entirely from organic building blocks, can possess high surface area and stability, and has a controllable composition and functionality. This review focuses on the application of POPs as photocatalysts in organic synthesis. For each reaction type, a representative material is discussed, with special attention to the mechanism of the reaction. Additionally, an overview is given, comparing POPs with other classes of photocatalysts, and critical conclusions and future perspectives are provided on this important field.

Versatile Palladium-catalyzed intramolecular cyclization to access new luminescent azaphosphaphenalene motifs.

Using a straightforward sequence of diphosphonylation and a Pd-catalysed concerted-metalation-deprotonation (CMD), a synthetic strategy towards polyaromatic phosphorus containing heterocycles was developed. Herein, we report the synthesis and characterization of new azaphosphaphenalenes, using easily accessible palladium catalysts and starting materials. The key tetrahydroquinoline intermediates of the reaction were synthesised via a fast and effective procedure and could be isolated as such, or further reacted towards the target polyaromatic structures. The obtained products showed interesting luminescent properties and their emission, excitation and quantum yields were evaluated.

Glioblastoma-Associated Mesenchymal Stem/Stromal Cells and Cancer-Associated Fibroblasts: Partners in Crime?

Tumor-associated mesenchymal stem/stromal cells (TA-MSCs) have been recognized as attractive therapeutic targets in several cancer types, due to their ability to enhance tumor growth and angiogenesis and their contribution to an immunosuppressive tumor microenvironment (TME). In glioblastoma (GB), mesenchymal stem cells (MSCs) seem to be recruited to the tumor site, where they differentiate into glioblastoma-associated mesenchymal stem/stromal cells (GA-MSCs) under the influence of tumor cells and the TME. GA-MSCs are reported to exert important protumoral functions, such as promoting tumor growth and invasion, increasing angiogenesis, stimulating glioblastoma stem cell (GSC) proliferation and stemness, mediating resistance to therapy and contributing to an immunosuppressive TME. Moreover, they could act as precursor cells for cancer-associated fibroblasts (CAFs), which have recently been identified in GB. In this review, we provide an overview of the different functions exerted by GA-MSCs and CAFs and the current knowledge on the relationship between these cell types. Increasing our understanding of the interactions and signaling pathways in relevant models might contribute to future regimens targeting GA-MSCs and GB-associated CAFs to inhibit tumor growth and render the TME less immunosuppressive.

Tuning the antimicrobial activity of microbial glycolipid biosurfactants through chemical modification.

Sophorolipids, glycolipid biosurfactants derived from microorganisms such as Starmerella bombicola, possess distinctive surface-active and bioactive properties, holding potential applications in cosmetics, pharmaceuticals and bioremediation. However, the limited structural variability in wild-type sophorolipids restricts their properties and applications. To address this, metabolic engineering efforts have allowed to create a portfolio of molecules. In this study, we went one step further by chemically modifying microbially produced sophorosides, produced by an engineered S. bombicola. Twenty-four new sophoroside derivatives were synthesized, including sophoroside amines with varying alkyl chain lengths (ethyl to octadecyl) on the nitrogen atom and their corresponding quaternary ammonium salts. Additionally, six different microbially produced glycolipid biosurfactants were hydrogenated to achieve fully saturated lipid tails. These derivatives, along with microbially produced glycolipids and three benchmark biosurfactants (di-rhamnolipids, alkyl polyglucosides, cocamidopropyl betaine), were assessed for antimicrobial activity against bacteria (Bacillus subtilis, Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, Pseudomonas aeruginosa) and yeast (Candida albicans). Results indicated that microbially produced glycolipids, such as bola sophorosides, acidic sophorolipids and acidic glucolipids exhibit selective antimicrobial activity against the test organisms. Conversely, lactonic sophorolipids, sophoroside amines and quaternary ammonium salts display a broad antimicrobial activity. N-octyl, N-dodecyl and N-octadecyl derivatives exhibit the lowest minimal inhibitory concentrations, ranging from 0.014 to 20.0 mg mL-1. This study demonstrates the potential synergy of thoughtful biotechnology and targeted chemistry to precisely tailor glycolipid biosurfactants to meet specific requirements across applications.

An in vitro experimental pipeline to characterize the epitope of a SARS-CoV-2 neutralizing antibody.

IMPORTANCE: The COVID-19 pandemic remains a significant public health concern for the global population; the development and characterization of therapeutics, especially ones that are broadly effective, will continue to be essential as severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) variants emerge. Neutralizing monoclonal antibodies remain an effective therapeutic strategy to prevent virus infection and spread so long as they recognize and interact with circulating variants. The epitope and binding specificity of a neutralizing anti-SARS-CoV-2 Spike receptor-binding domain antibody clone against many SARS-CoV-2 variants of concern were characterized by generating antibody-resistant virions coupled with cryo-EM structural analysis and VSV-spike neutralization studies. This workflow can serve to predict the efficacy of antibody therapeutics against emerging variants and inform the design of therapeutics and vaccines.

Chemical induction of hypocotyl rooting reveals extensive conservation of auxin signalling controlling lateral and adventitious root formation.

Upon exposure to light, etiolated Arabidopsis seedlings form adventitious roots (AR) along the hypocotyl. While processes underlying lateral root formation are studied intensively, comparatively little is known about the molecular processes involved in the initiation of hypocotyl AR. AR and LR formation were studied using a small molecule named Hypocotyl Specific Adventitious Root INducer (HYSPARIN) that strongly induces AR but not LR formation. HYSPARIN does not trigger rapid DR5-reporter activation, DII-Venus degradation or Ca2+ signalling. Transcriptome analysis, auxin signalling reporter lines and mutants show that HYSPARIN AR induction involves nuclear TIR1/AFB and plasma membrane TMK auxin signalling, as well as multiple downstream LR development genes (SHY2/IAA3, PUCHI, MAKR4 and GATA23). Comparison of the AR and LR induction transcriptome identified SAURs, AGC kinases and OFP transcription factors as specifically upregulated by HYSPARIN. Members of the SAUR19 subfamily, OFP4 and AGC2 suppress HYS-induced AR formation. While SAUR19 and OFP subfamily members also mildly modulate LR formation, AGC2 regulates only AR induction. Analysis of HYSPARIN-induced AR formation uncovers an evolutionary conservation of auxin signalling controlling LR and AR induction in Arabidopsis seedlings and identifies SAUR19, OFP4 and AGC2 kinase as novel regulators of AR formation.

Drug discovery-based approach identifies new nitrification inhibitors.

Nitrogen (N) fertilization is crucial to sustain global food security, but fertilizer N production is energy-demanding and subsequent environmental N losses contribute to biodiversity loss and climate change. N losses can be mitigated be interfering with microbial nitrification, and therefore the use of nitrification inhibitors in enhanced efficiency fertilizers (EEFs) is an important N management strategy to increase N use efficiency and reduce N pollution. However, currently applied nitrification inhibitors have limitations and do not target all nitrifying microorganisms. Here, to identify broad-spectrum nitrification inhibitors, we adopted a drug discovery-based approach and screened 45,400 small molecules on different groups of nitrifying microorganisms. Although a high number of potential nitrification inhibitors were identified, none of them targeted all nitrifier groups. Moreover, a high number of new nitrification inhibitors were shown to be highly effective in culture but did not reduce ammonia consumption in soil. One archaea-targeting inhibitor was not only effective in soil, but even reduced - when co-applied with a bacteria-targeting inhibitor - ammonium consumption and greenhouse gas emissions beyond what is achieved with currently applied nitrification inhibitors. This advocates for combining different types of nitrification inhibitors in EEFs to optimize N management practices and make agriculture more sustainable.

Engineering of Phenylpyridine- and Bipyridine-Based Covalent Organic Frameworks for Photocatalytic Tandem Aerobic Oxidation/Povarov Cyclization.

Covalent organic frameworks (COFs) are emerging as a new class of photoactive organic semiconductors, which possess crystalline ordered structures and high surface areas. COFs can be tailor-made toward specific (photocatalytic) applications, and the size and position of their band gaps can be tuned by the choice of building blocks and linkages. However, many types of building blocks are still unexplored as photocatalytic moieties and the scope of reactions photocatalyzed by COFs remains quite limited. In this work, we report the synthesis and application of two bipyridine- or phenylpyridine-based COFs: TpBpyCOF and TpPpyCOF. Due to their good photocatalytic properties, both materials were applied as metal-free photocatalysts for the tandem aerobic oxidation/Povarov cyclization and α-oxidation of N-aryl glycine derivatives, with the bipyridine-based TpBpyCOF exhibiting the highest activity. By expanding the range of reactions that can be photocatalyzed by COFs, this work paves the way toward the more widespread application of COFs as metal-free heterogeneous photocatalysts as a convenient alternative for commonly used homogeneous (metal-based) photocatalysts.

An in vitro experimental pipeline to characterize the binding specificity of SARS-CoV-2 neutralizing antibodies.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has led to over 760 million cases and >6.8 million deaths worldwide. We developed a panel of human neutralizing monoclonal antibodies (mAbs) targeting the SARS-CoV-2 Spike protein using Harbour H2L2 transgenic mice immunized with Spike receptor binding domain (RBD) (1). Representative antibodies from genetically-distinct families were evaluated for inhibition of replication-competent VSV expressing SARS-CoV-2 Spike (rcVSV-S) in place of VSV-G. One mAb (denoted FG-10A3) inhibited infection of all rcVSV-S variants; its therapeutically-modified version, STI-9167, inhibited infection of all tested SARS-CoV-2 variants, including Omicron BA.1 and BA.2, and limited virus proliferation in vivo (1). To characterize the binding specificity and epitope of FG-10A3, we generated mAb-resistant rcVSV-S virions and performed structural analysis of the antibody/antigen complex using cryo-EM. FG-10A3/STI-9167 is a Class 1 antibody that prevents Spike-ACE2 binding by engaging a region within the Spike receptor binding motif (RBM). Sequencing of mAb-resistant rcVSV-S virions identified F486 as a critical residue for mAb neutralization, with structural analysis revealing that both the variable heavy and light chains of STI-9167 bound the disulfide-stabilized 470-490 loop at the Spike RBD tip. Interestingly, substitutions at position 486 were later observed in emerging variants of concern BA.2.75.2 and XBB. This work provides a predictive modeling strategy to define the neutralizing capacity and limitations of mAb therapeutics against emerging SARS-CoV-2 variants. Importance: The COVID-19 pandemic remains a significant public health concern for the global population; development and characterization of therapeutics, especially ones that are broadly effective, will continue to be essential as SARS-CoV-2 variants emerge. Neutralizing monoclonal antibodies remain an effective therapeutic strategy to prevent virus infection and spread with the caveat that they interact with the circulating variants. The epitope and binding specificity of a broadly neutralizing anti-SARS-CoV-2 Spike RBD antibody clone against many SARS-CoV-2 VOC was characterized by generating antibody-resistant virions coupled with cryo-EM structural analysis. This workflow can serve to predict the efficacy of antibody therapeutics against emerging variants and inform the design of therapeutics and vaccines.

Metagenomics-enabled reverse-genetics assembly and characterization of myotis bat morbillivirus.

Morbilliviruses are among the most contagious viral pathogens of mammals. Although previous metagenomic surveys have identified morbillivirus sequences in bats, full-length morbilliviruses from bats are limited. Here we characterize the myotis bat morbillivirus (MBaMV) from a bat surveillance programme in Brazil, whose full genome was recently published. We demonstrate that the fusion and receptor binding protein of MBaMV utilize bat CD150 and not human CD150, as an entry receptor in a mammalian cell line. Using reverse genetics, we produced a clone of MBaMV that infected Vero cells expressing bat CD150. Electron microscopy of MBaMV-infected cells revealed budding of pleomorphic virions, a characteristic morbillivirus feature. MBaMV replication reached 103-105 plaque-forming units ml-1 in human epithelial cell lines and was dependent on nectin-4. Infection of human macrophages also occurred, albeit 2-10-fold less efficiently than measles virus. Importantly, MBaMV is restricted by cross-neutralizing human sera elicited by measles, mumps and rubella vaccination and is inhibited by orally bioavailable polymerase inhibitors in vitro. MBaMV-encoded P/V genes did not antagonize human interferon induction. Finally, we show that MBaMV does not cause disease in Jamaican fruit bats. We conclude that, while zoonotic spillover into humans may theoretically be plausible, MBaMV replication would probably be controlled by the human immune system.

Nipah Virus Bangladesh Infection Elicits Organ-Specific Innate and Inflammatory Responses in the Marmoset Model.

The common marmoset (Callithrix jacchus) is increasingly recognized as an ideal nonhuman primate (NHP) at high biocontainment due to its smaller size and relative ease of handling. Here, we evaluated the susceptibility and pathogenesis of Nipah virus Bangladesh strain (NiVB) infection in marmosets at biosafety level 4. Infection via the intranasal and intratracheal route resulted in fatal disease in all 4 infected marmosets. Three developed pulmonary edema and hemorrhage as well as multifocal hemorrhagic lymphadenopathy, while 1 recapitulated neurologic clinical manifestations and cardiomyopathy on gross pathology. Organ-specific innate and inflammatory responses were characterized by RNA sequencing in 6 different tissues from infected and control marmosets. Notably, a unique transcriptome was revealed in the brainstem of the marmoset exhibiting neurological signs. Our results provide a more comprehensive understanding of NiV pathogenesis in an accessible and novel NHP model, closely reflecting clinical disease as observed in NiV patients.

Acidic sophorolipid and antimicrobial peptide based formulation as antimicrobial and antibiofilm agents.

Antimicrobial peptides (AMPs) are considered promising candidates to treat various infections in soft tissues and skin. However, no effective treatment based on AMPs has been reached to clinics due to their instability in serum and wounds. Biosurfactants such as acidic sophorolipids (ASLs) of very high concentrations (equal or above 5 mg/mL) have been demonstrated to be antimicrobial agents, however these concentrations might induce cytotoxic effects to human cells. Here, we have demonstrated the synergistic antimicrobial effect of ASL nanoparticles (NPs) and LL37 peptides (below their minimum inhibitory concentrations; MICs) to eradicate Gram-positive and Gram-negative bacteria in human serum (HS) and in the presence of trypsin. The formulations containing ASL NPs (500 µg/mL) and LL37 peptides (15-25 µg/mL) effectively kill wide strains of bacteria in 5 % HS and the presence of trypsin. Moreover, the combination of ASL NPs (500 µg/mL) and LL37 peptides (15 µg/mL) prevents the formation of S. aureus biofilm and eradicates the one-day old biofilm. Importantly, the combination of ASL NPs and LL37 peptides severely damages the cell membrane of Escherichia coli (E. coli) as shown by atomic force microscopy (AFM). The combination of ASL NPs and LL37 peptides rapidly damages the outer (OM) and inner membrane (IM) of E. coli, while ASL NPs (1000 µg/mL) alone slowly compromise the integrity of the bacterial membrane. Importantly, the combination of ASL NPs and LL37 peptides is biocompatible to human keratinocyte cells (HaCaTs) and human umbilical vein endothelial cells (HUVECs), and induces the expression of anti-inflammatory cytokine in macrophages. Overall, ASL NPs in combination with LL37 peptides might be developed as an effective topical formulation to prevent bacterial infections in the skin.